In mammals, sleep is divided into two broad types: rapid eye movement (REM) and non-rapid eye movement (NREM or non-REM) sleep. The American Academy of Sleep Medicine (AASM) further divides NREM into three stages: N1, N2, and N3, the last of which is also called delta sleep or slow-wave sleep (SWS). (see, e.g., Silber M H, et al., 2007, J. of Clin. Sleep Med., 3 (2): 121-31). This revised scoring introduced in 2007 combined the former stage III and stage IV (referred to in the Example hereinbelow) into the new stage N3.
Sleep proceeds in cycles of REM and NREM, the order normally being N1→N2→N3→N2→REM. There is a greater amount of deep sleep (stage N3) earlier in the sleep cycle, while the proportion of REM sleep increases later in the sleep cycle and just before natural awakening. In humans, each sleep cycle lasts on average from 90 to 110 minutes.
Stage N1 refers to the transition of the brain from alpha waves having a frequency of 8-13 Hz (common in the awake state) to theta waves having a frequency of 4-7 Hz. This stage is sometimes referred to as somnolence or drowsy sleep. Sudden twitches and hypnic jerks, also known as positive myoclonus, may be associated with the onset of sleep during N1. Some people may also experience hypnagogic hallucinations during this stage. During N1, the subject loses some muscle tone and most conscious awareness of the external environment.
Stage N2 is characterized by sleep spindles ranging from 11-16 Hz (most commonly 12-14 Hz) and K-complexes. During this stage, muscular activity as measured by EMG decreases, and conscious awareness of the external environment disappears. This stage occupies 45-55% of total sleep in adults.
Stage N3 (deep or slow-wave sleep) is characterized by the presence of a minimum of 20% delta waves ranging from 0.5-2 Hz and having a peak-to-peak amplitude >75 μV. This is the stage in which parasomnias such as night terrors, nocturnal enuresis, sleepwalking, and somniloquy occur. Many illustrations and descriptions still show a stage III with 20-50% delta waves and a stage IV with greater than 50% delta waves; these have been combined as stage N3.
Rapid eye movement sleep, or REM sleep, accounts for 20-25% of total sleep time in most human adults. The criteria for REM sleep include rapid eye movements as well as a rapid low-voltage EEG. Most memorable dreaming occurs in this stage. At least in mammals, a descending muscular atonia is seen. Such paralysis may be necessary to protect organisms from self-damage through physically acting out scenes from the often-vivid dreams that occur during this stage.
In older adults, sleep is disturbed with more awakenings, less SWS and less REM sleep. The older population also is the primary user of hypnotics (see, e.g., Mendelson, Human Sleep: Research and Clinical Care, Plenum Press, New York, p. 436, 1987), although it is widely accepted that chronic hypnotic use has generally deleterious effects (see, e.g., Prinz, J. Clin. Neurophysiol., 12:139-146, 1995).
Commercially available hypnotics, including the benzodiazepines, improve sleep efficiency but do not consistently increase either SWS or REM sleep. See, e.g., Gaillard, in Principles And Practice of Sleep Medicine, Kryger, Roth, Dement (eds), W.B. Saunders, Philadelphia, Pa., p. 349-354, 1994.
Hypnotics (e.g., benzodiazepines and Z-compounds) act on sleep efficiency, but do not improve, but rather tend to worsen, sleep patterns. Thus these drugs may be useful for patients showing troubles going to sleep, i.e., falling asleep. Because of their modification of the sleep pattern however, they do not prove particularly useful for patients who have no problems going to sleep, but who wake up during the night, e.g., suffer from mid-sleep period awakenings.
Thus, there remains a need for effective treatments for perturbed sleep patterns.
The effects of progesterone on sleep have been studied by a number of groups, and their results tend to diverge. In 1997, Friess et al., Am. J. Physiol., 1997, 272: E885-91, reported an effect on sleep patterns in men orally administered 300 mg progesterone, akin to those induced by agonistic modulators of the GABA(A) receptors complex, and especially in its modification of the sleep pattern: increase of stage N2 time and decrease of stage N3 time and of REM sleep. In 2005, Heinrich and Wolf, Neuropsychobiology, 2005, 52:17-23, reported results of a questionnaire-based study that found that estradiol and progesterone had no effect on subjective sleep quality in hysterectomized women administered 2 mg estradiol valerate and 100 mg progesterone. In 2008, Schüssler et al., Psychoneuroendocrinology, 2008, 33:1124-1131, reported a decrease of intermittent time spent awake and increase in REM sleep in the first third of the night in post-menopausal women administered 300 mg progesterone; however, there were no significant differences between baseline, placebo and progesterone in the total duration of REM. Stage 2 or SWS, or in the absolute power spectra delta, theta, sigma, alpha and beta.